Understudied factors in drug‐coated balloon design and evaluation: A biophysical perspective

Abstract Drug‐coated balloon (DCB) percutaneous interventional therapy allows for durable reopening of the narrowed lumen via physical tissue expansion and local anti‐restenosis drug delivery, providing an alternative to traditional uncoated balloons or a permanent indwelling implant such as a conventional metallic drug‐eluting stent. While DCB‐based treatment of peripheral arterial disease (PAD) has been incorporated into clinical guidelines, DCB use has been recently curtailed due to reports that showed evidence of increased mortality risk in patients treated with paclitaxel (PTX)‐coated balloons. Given the United States Food and Drug Administration's 2019 consequent warning regarding PTX‐eluting DCBs and the subsequent marked reduction in clinical DCB use, there is now a critical need to better understand the compositional and mechanical factors underlying DCB efficacy and safety. Most work to date on DCB refinement has focused on designing both the enabling balloon catheter and alternate coatings composed of various drugs and excipients, followed by device evaluation in preclinical and clinical studies. We contend that improvement in DCB performance will require a better understanding of the biophysical factors operative during and following balloon deployment, and moreover that the elaboration and demonstrated control of these factors are needed to address current concerns with DCB use. This article provides a perspective on the biophysical interactions that govern DCB performance and offers new design strategies for the development of next‐generation DCB devices.


| INTRODUCTION
The prevalence and significance of peripheral artery disease (PAD) continue to increase in our aging population and remains a major cause of critical limb ischemia and amputations. [1][2][3] However, current endovascular interventions for PAD, such as percutaneous transluminal angioplasty (PTA) alone or in conjunction with endovascular stents, are limited by high restenosis rates ranging from 39% to 60% at 1 year. 4,5 Moreover, long lesions within the infrainguinal vasculature and device fracture rates limit the efficacy of stent-based technologies. 6,7 Drug-coated balloon (DCB) therapy, which is an angioplasty balloon-based treatment that delivers an antiproliferative/anti-restenosis payload to the artery wall, has become the effective standard-of-care treatment for PAD, [8][9][10] 12 This decision has markedly reduced clinical DCB use, 13 potentially leading to higher restenosis rates following endovascular interventions that now rely on conventional balloons or bare metal stents.
Notably, a causal mechanism linking PTX-based DCBs and mortality has yet to be determined, which is critical in understanding the validity of the statistical signal. Attempts to establish a dose-response relationship have been unsuccessful, 14 and specific causes of death between those exposed to PTX-coated devices versus uncoated devices have not revealed a causal association. 15 Both the failure to determine a mechanistic relationship with DCBs and mortality, coupled with the dramatic FDA response to the Katsanos' study, underscores our limited understanding of how DCB devices work and the conditions that can lead to untoward scenarios. While emerging data suggests the potential for PTX-based DCBs to be safe clinically, [16][17][18] and to serve as a plaque stabilizing therapy, 19 the presently halted use of DCBs serves as an impetus to obtain a deeper understanding of the mechanisms governing DCB function and define the role of biophysical factors in balloon transfer of free drug and/or coating to the arterial wall, and subsequent drug transport, retention, and distribution.
Several factors spanning the design (preprocedural), deployment (intra-procedural), and follow-up (post-procedural) phases need to be understood to fully understand and evaluate DCB efficacy and safety.
With a goal of maximizing the degree of anti-restenosis agent (e.g., PTX) transfer and retention into the target lesion, many studies have focused on optimizing the design of the balloon catheter, including its geometry and elastic mechanical properties, as well as alternate excipient-drug combinations for coating formation. 20 A few studies have also explored antiproliferative compounds belonging to the "limus" family as drugs of choice for DCB therapy. [21][22][23][24] Additionally, other studies have focused on lesion preparation prior to DCB deployment, [25][26][27] with the goals of modifying calcified plaque, facilitating balloon expansion, and promoting maximal DCB-surface contact with the arterial wall. The design of device constituents and strategies for lesion preparation are key factors associated with the pre-procedural phase. The post-procedural phase has been examined in both experimental and clinical settings, in which identified endpoints/factors include the degree of restored lumen patency, offtarget drug effects, the efficiency of drug delivery, dissolution, convection, diffusion and drug binding, 21 barriers to absorption, and interaction between the drug, delivery vehicle, and overall drug pharmacokinetics within the arterial wall. 28 Conversely to these well-studied pre-and post-procedural phases, we submit that the intra-procedural phase, where the device meets the artery, has been understudied. Moreover, evidence suggests that the role of underlying biophysical events operative during this phase can be generalized across candidate DCBs and will prove to be deterministic of drug transfer and overall device efficacy.
Below we identify the general problems limiting current DCBs, highlight key factors and findings germane to the pre-and postprocedural phases, present a detailed breakdown of the dynamic interactions during DCB deployment by viewing it primarily as a sequence of biophysical events, and propose future directions to improve DCB efficacy.

| Approved DCBs
There are several experimental, animal, and human studies focused on DCB design, development, and evaluation. 29 DCBs have been considered for deployment in the coronary circulation (to treat both in-stent restenosis and de novo lesions; mainly outside the United States), [30][31][32][33] in the peripheral circulation (for both femoropopliteal [within the United States] and below-the-knee indications), [34][35][36][37][38][39] and to a lesser degree in arteriovenous fistula and grafts (AVF/AVG). [40][41][42][43] While it is not practical to cover all potential clinical applications in this article, we highlight some of the well-known DCBs that have • Ranger™: The device was approved for lesions with up to 180 mm in length within reference vessel diameters of 4-7 mm. As above, this device also contains paclitaxel with a nominal dose density of 2 μg/mm 2 , and acetyl tributyl citrate, which is a plasticizer as its excipient. In the RANGER SFA trial, 39 the DCB group had a greater primary patency rate at 12 months compared to the control group, and this result was associated with low revascularization rate and good clinical outcomes.

| Drug and coating transfer inefficiencies reduce DCB efficacy
As noted above, all FDA-approved DCBs contain PTX as their drug component, with various excipients that serve as drug carriers. During the procedure, the balloon catheter advances from the arterial insertion site to the target artery application site. During this step, a reasonable amount of coating/drug can potentially be lost to the F I G U R E 1 Stages of DCB deployment. The DCB procedure includes balloon placement at the target site (top), balloon inflation (middle), and balloon deflation/retraction (bottom). During placement, the balloon is guided to and positioned at the site of plaque accumulation. During inflation, the plaque is compressed, and coating constituents (coating/drug) are transferred from the balloon surface to the arterial wall. During deflation/retraction, some transferred constituents adhere to/are adsorbed by the arterial wall, while some is lost to the circulation.
circulation, representing the first mode of efficiency reduction. 46 After the balloon reaches the site and during the balloon inflation, the coating/drug undergoes a net diffusive transport from the catheter to the vessel wall due to the concentration gradient established across the coating-vessel interface ( Figure 1). Despite significant excipient/ coating variability among proposed DCBs, all devices exhibit inefficient total drug transfer to the tissue during the procedural window (approximately <10% of total drug delivered on-target). 47 Moreover, a few pre-clinical studies have shown that only a small portion of the coating (8%) is transferred during balloon inflation, 48 and almost 90% of the delivered PTX releases from the arterial wall into the systemic circulation within 48 hours, increasing the potential for systemic toxicity. 47 To compensate for inefficient drug transfer and subsequent wash-off, coatings are designed with high initial drug concentrations that ensure therapeutic dosing is nevertheless achieved. Indeed, a multitude of previous studies have shown that with this approach, drug concentrations in local tissue are such that tissue binding capacity is reached within seconds after balloon inflation. 49 Due to PTX's well-known pharmacological properties, namely its binding/transport kinetics and high binding specificity, 50-52 the antiproliferative effects subsequently persist for prolonged periods. However, we postulate that the compensatory design strategy of high initial coating drug con- However, initially transferred coating that later is dislodged by the convective forces of pulsatile blood flow may lead to drug/coating embolization, a process which represents a second major risk factor associated with DCB use. In analogy to drug transfer efficiency, increasing the efficiency of coating transfer to the vessel wall would enable DCB designs with less coating content and thus lower embolic potential.
Taken together, the transfer inefficiencies of DCB constituents (drug and coating) to the arterial wall are likely culprits in limiting DCB efficacy. Thus, while there are numerous directions for DCB refinement, including strategies for patient-and lesion-specific dosing, alternative drugs for DCB applications, and excipient selection, enhancing drug and coating transfer efficiency can be viewed as an independent performance objective that can be readily quantified and used as a basis for iterative device design.

| BIOPHYSICAL FACTORS IN DCB DEPLOYMENT
3.1 | DCB deployment procedure as a sequence of biophysical events From introduction into the circulation to retraction from the patient, DCBs undergo a series of biophysical events that cumulatively influence the efficiency of drug/coating transfer to the arterial wall. Firstly, the catheter guidance to and positioning within the targeted vasculature relies on adequate device stiffness and steerability. Although not directly determinate of transfer efficiency, precision placement and control of device positioning is a prerequisite for successful intervention. Next, upon unsheathing, the coating is exposed to local flowinduced shear stress that promotes constituent wash-off and mass loss to the circulation. Once the balloon is positioned and unsheathed, the dynamic inflation process is initiated, and a coating-arterial wall interface is formed. Subsequent balloon inflation (beyond that required for initial contact up to that required to reach the balloon operating diameter) transmits a radial force through this interface and results in a bi-axial deformation of the arterial wall, characterized by a radial compression and circumferential tension that reestablishes the arterial lumen. The coating also undergoes circumferential tension during balloon inflation, and depending on its microstructure and mechanical properties, may also experience a radial compression upon contact with the arterial wall. In comparison to physiological arterial loading, complete balloon inflation is achieved under extremely high inflation pressures. 54 As a result, in the fully inflated configuration when the balloon outer diameter equals the artery inner diameter, this dimension represents a kinematic constraint on the arterial deformation. Even when appropriately sized balloons are used to proportionally match the vessel size, the arterial wall exhibits significant viscoelastic behavior in non-physiological loading domains, and this imposed kinematic constraint may induce a mechanical creep response that modulates the interface throughout the inflation period.
Taken together, these complex mechanical events will dictate the transient coating-arterial wall interface operative during DCB inflation.
Via this dynamic interface that the functionally central diffusive transport of drug from the coating to the arterial wall occurs, the deformation of both the coating and arterial wall will dictate key geometric factors in drug/coating transfer efficiencies, namely coatingartery contact area and coating penetration depth into the arterial wall. Upon balloon deflation/device retraction, the adhesive forces developed between the coating and arterial wall are placed in conflict with the cohesive forces in the coating itself and the adhesive force between the coating and the balloon, wherein the relative magnitude of these forces will determine if coating is transferred and ultimately retained at the treatment site ( Figure 2). In the following sections, we will consider each of these biophysical events in detail and focus on their potential role in drug/coating transfer efficiency with DCB deployment.

| Interfacial formation and dissociation
At the microstructural level, current coatings have significant geometrical variance which in turn impacts contact mechanics and interfacial formation with arterial tissue during DCB inflation. 20 For example, experimental urea-based coatings have a conical, needle-like microstructure, while shellac-based coatings are largely composed of spherical elements (Figure 3). Moreover, these microstructural geometries present a range of characteristic length scales that would further impact local coating-tissue interactions. In the formation of the tissuecoating interface, it is likely that the needle-like urea microstructure, particularly for the subset of aggregate coating domains oriented perpendicularly to the balloon surface, will promote penetration into the tissue due to a small contact area over which the inflation force is transmitted. Conversely, a spherical microstructure will have a comparatively high contact area but have less tendency to penetrate the arterial wall. While the impact of these microstructural differences on drug transfer and contact mechanics has been explained for a subset of experimental coatings, 20 it is not immediately clear which of these phenomena will ultimately lead to enhanced therapeutic gains, as both

| Providing a durable post-procedural anti-restenotic effect
Once the balloon is deflated, both transferred and residual coating domains are exposed to the hemodynamic environment. The post-  shown that adequate lesion pretreatment enhances the drug penetration into the vessel wall, which promotes and increases the antirestenotic properties. 25 We postulate that such improved efficiency can be attributed to the changes in the biophysical footprint of the prepared vessel in contrast to the lesion with unexpanded plaque.

| Lesion preparation
While studies have indicated that vessel preparation minimizes the risk of dissections, maximizes the luminal gain, and prepares the vessel bed for local drug delivery, 26,27 it is important to also quantify the biophysical significance of lesion preparation, which can inform better DCB design.

| Bench-top studies in DCB design and evaluation
Accepting the notion that intra-procedural transfer efficiencies of  (Figure 6), to process data generated from coarse meshes to predict results derived from highly-refined meshesthereby drastically increasing the efficiency in the computational modeling workflow. 69 However, it must be noted that all the studies to-date, except one, 70  Given the complex interplay between the balloon design, flow, and drug parameters, there is an opportunity for computational modeling and simulation to be deployed in sophisticated optimization strategies for targeting improved device performance. As an example, we know that sufficient inflation pressure is required to both break through stiff atherosclerotic lesions and ensure proper contact area with the balloon surface. However, this high inflation pressure comes along with the risk of acute trauma to the blood vessel or even severe dissection. 72 Future studies focused on evaluating the relationship between inflation pressure and the local stress within the arterial wall would reveal the proper operating conditions for inflation pressure along with lesion preparation to ensure acute safety and efficacy.
Furthermore, given the short residence time in the lumen as compared to drug-eluting stents, drug-eluting/coated balloons usually rely on high doses of drug coated along the exterior surface of the balloon.
As a result, care must be taken to design coatings with sufficient adherence to the balloon to prevent wash-off of the coating resulting in systemic toxicity and/or embolism. To address this concern, computational fluid dynamics studies could be deployed to provide insight into the shear stresses that the surface is exposed to in the period between unsheathing of the balloon and the moment it meets the vessel wall to obtain performance benchmarks for the strength of the coating adhesion. Finally, it is well understood that the efficacy of drug deposition is highly dependent on the contact pressure between the balloon and the surface of the lesion. Lee et al. presented a novel balloon design with a linear micropattern along the surface of the balloon and demonstrated that this design resulted in higher drug deposition in vivo as compared to traditional designs with a smooth cylindrical surface. 73 Taken together with our understanding that the microstructural elements of the drug coating can be modulated based on its composition, 20 it stands to reason that there is an optimal solution which appropriately strikes the balance between micro-scale surface roughness and contact area.

ACKNOWLEDGMENTS
This project was supported by grants from the National Institutes of Health (R01-HL159620, R21-CA253498) and the American Heart Association (17SDG33670323, 20SFRN35460031).

PEER REVIEW
The peer review history for this article is available at https://publons.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.